Objectives: Obesity is a major epidemic in our population and has emerged as a primary health concern. Consumption of a high fat, high sugar (HFHS) diet can specifically lead to gut dysbiosis, increased inflammation, and neuroinflammation. Interestingly, sex differences in the response to a HFHS diet are emerging. In this study, we investigated the effects of a HFHS diet compared to a low fat, low sugar (LFLS) diet in 8 week old male and female C57Bl/6 mice.Methods: The diet was administered for 14 weeks; body weights and food consumption were evaluated weekly.Results: Male and female mice fed the HFHS diet gained significantly more weight than LFLS-fed mice. However, in agreement with previous studies, males gained significantly more weight on the HFHS diet compared to females fed the same diet. Importantly, we determined significant sex and diet-induced differences to gut microbiome composition using next generation Illumina sequencing. We also observed significantly less astrocyte densitometry and no significant change to microglial morphology in the hypothalamus of Female HFHS compared to Female LFLS. On the other hand, Male HFHS revealed no change to hypothalamic astrogliosis, but increased microgliosis compared to Male LFLS.Discussion: In this study, we determined sex and diet-induced differences in both the gut and the brain, however, future studies will need to be performed in order to test the direct role of the gut microbiome to weight gain and neuroinflammation in male and female mice.